bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2023‒11‒12
twelve papers selected by
Lara Paracchini, Humanitas Research
  1. Shallow whole genome sequencing approach to detect Homologous Recombination Deficiency in the PAOLA-1/ENGOT-OV25 phase-III trial.
  2. Extensive mutational ctDNA profiles reflect High-grade serous cancer tumors and reveal emerging mutations at recurrence.
  3. Homologous recombination deficiency (HRD) testing on cell-free tumor DNA from peritoneal fluid.
  4. Surgery and HIPEC in relapse for all patients with ovarian cancer?
  5. Opportunistic salpingectomy between 2017 and 2020: A descriptive analysis.
  6. Shallow whole genome re-sequencing to precisely predict benefit from PARP inhibitor.
  7. Pembrolizumab plus chemotherapy for pleural mesothelioma.
  8. Circulating cell-free DNA as a diagnostic and prognostic marker for cervical cancer.
  9. Low-grade serous ovarian carcinoma: a brief overview of the histopathologic features and differential diagnosis.
  10. Editorial: Translational research for better diagnosis and treatment of endometrial cancer.
  11. Most large structural variants in cancer genomes can be detected without long reads.
  12. Metronomic chemotherapy in ovarian cancer.
  1. Oncogene. 2023 Nov 09.
    Shallow whole genome sequencing approach to detect Homologous Recombination Deficiency in the PAOLA-1/ENGOT-OV25 phase-III trial.
    Celine Callens, Manuel Rodrigues, Adrien Briaux, Eleonore Frouin, Alexandre Eeckhoutte, Eric Pujade-Lauraine, Victor Renault, Dominique Stoppa-Lyonnet, Ivan Bieche, Guillaume Bataillon, Lucie Karayan-Tapon, Tristan Rochelle, Florian Heitz, Sabrina Chiara Cecere, Maria Jesús Rubio Pérez, Christoph Grimm, Trine Jakobi Nøttrup, Nicoletta Colombo, Ignace Vergote, Kan Yonemori, Isabelle Ray-Coquard, Marc-Henri Stern, Tatiana Popova.
      The bevacizumab (bev)/olaparib (ola) maintenance regimen was approved for BRCA1/2-mutated (BRCAmut) and Homologous Recombination Deficient (HRD) high-grade Advanced Ovarian Cancer (AOC) first line setting, based on a significantly improved progression-free survival (PFS) compared to bev alone in the PAOLA-1/ENGOT-ov25 trial (NCT02477644), where HRD was detected by MyChoice CDx PLUS test. The academic shallowHRDv2 test was developed based on shallow whole-genome sequencing as an alternative to MyChoice. Analytical and clinical validities of shallowHRDv2 as compared to MyChoice on 449 PAOLA-1 tumor samples are presented. The overall agreement between shallowHRDv2 and MyChoice was 94% (369/394). Less non-contributive tests were observed with shallowHRDv2 (15/449; 3%) than with MyChoice (51/449; 11%). Patients with HRD tumors according to shallowHRDv2 (including BRCAmut) showed a significantly prolonged PFS with bev+ola versus bev (median PFS: 65.7 versus 20.3 months, hazard ratio (HR): 0.36 [95% CI: 0.24-0.53]). This benefit was significant also for BRCA1/2 wild-type tumors (40.8 versus 19.5 months, HR: 0.45 [95% CI: 0.26-0.76]). ShallowHRDv2 is a performant, clinically validated, and cost-effective test for HRD detection.
    DOI:  https://doi.org/10.1038/s41388-023-02839-8
  2. Transl Oncol. 2023 Nov 02. pii: S1936-5233(23)00200-0. [Epub ahead of print]39 101814
    Extensive mutational ctDNA profiles reflect High-grade serous cancer tumors and reveal emerging mutations at recurrence.
    Giovanni Marchi, Anna Rajavuori, Mai T N Nguyen, Kaisa Huhtinen, Sinikka Oksa, Sakari Hietanen, Sampsa Hautaniemi, Johanna Hynninen, Jaana Oikkonen.
      OBJECTIVE: Circulating tumor DNA (ctDNA) offers a minimally-invasive alternative to study genomic changes in recurrent malignancies. With a high recurrence rate, the overall survival in high-grade serous ovarian carcinoma (HGSC) has remained low. Our objectives were to determine whether ctDNA from plasma adequately represents HGSC, and to find mutational changes at relapse suggesting therapy options that could alter patient outcome.METHODS: We collected 152 longitudinal plasma and 92 fresh tissue samples from 29 HGSC patients, sequencing and detecting mutations with a gene panel of more than 700 cancer-related genes. Tumor content was measured using TP53 VAF. We analyzed the concordance between the mutations in tissue and plasma samples and calculated correlations to patient outcomes. We also searched for novel mutations appearing at relapse.
    RESULTS: The concordance rate between mutations in plasma compared to tumor tissue was 83 % at diagnosis and 90 % at relapse. CtDNA was released similarly from the tubo-ovarian tumors, intra-abdominal metastases and ascites. CtDNA release was high when CA-125 level was elevated. The TP53 VAF in ctDNA from plasma samples before the third cycle of primary chemotherapy showed a negative correlation to patient outcome. At relapse, 19 novel, pathogenic DNA mutations appeared, suggesting possible actionable alterations and biological mechanisms related to chemoresistance.
    CONCLUSION: Relapse ctDNA samples reflect tissue samples well and longitudinal sampling provides a timely source for mutational profiling. The emerging genetic mutations at recurrence propose that ctDNA accurately represents the widespread disease and provides possibilities for personalized therapy options.
    Keywords:  DNA mutations; High-grade serous ovarian carcinoma; Liquid biopsy; Targeted sequencing; ctDNA
    DOI:  https://doi.org/10.1016/j.tranon.2023.101814
  3. Mol Cancer. 2023 Nov 06. 22(1): 178
    Homologous recombination deficiency (HRD) testing on cell-free tumor DNA from peritoneal fluid.
    Cyril Roussel-Simonin, Felix Blanc-Durand, Roseline Tang, Damien Vasseur, Audrey Le Formal, Laure Chardin, Elisa Yaniz, Sébastien Gouy, Amandine Maulard, Stéphanie Scherier, Claire Sanson, Ludovic Lacroix, Sophie Cotteret, Lea Mauny, François Zaccarini, Etienne Rouleau, Alexandra Leary.
      BACKGROUND: Knowing the homologous recombination deficiency (HRD) status in advanced epithelial ovarian cancer (EOC) is vital for patient management. HRD is determined by BRCA1/BRCA2 pathogenic variants or genomic instability. However, tumor DNA analysis is inconclusive in 15-19% of cases. Peritoneal fluid, available in > 95% of advanced EOC cases, could serve as an alternative source of cell-free tumor DNA (cftDNA) for HRD testing. Limited data show the feasibility of cancer panel gene testing on ascites cfDNA but no study, to date, has investigated HRD testing.METHODS: We collected ascites/peritoneal washings from 53 EOC patients (19 from retrospective cohort and 34 from prospective cohort) and performed a Cancer Gene Panel (CGP) using NGS for TP53/HR genes and shallow Whole Genome Sequencing (sWGS) for genomic instability on cfDNA.
    RESULTS: cfDNA was detectable in 49 out of 53 patients (92.5%), including those with limited peritoneal fluid. Median cfDNA was 3700 ng/ml, with a turnaround time of 21 days. TP53 pathogenic variants were detected in 86% (42/49) of patients, all with HGSOC. BRCA1 and BRCA2 pathogenic variants were found in 14% (7/49) and 10% (5/49) of cases, respectively. Peritoneal cftDNA showed high sensitivity (97%), specificity (83%), and concordance (95%) with tumor-based TP53 variant detection. NGS CGP on cftDNA identified BRCA2 pathogenic variants in one case where tumor-based testing failed. sWGS on cftDNA provided informative results even when tumor-based genomic instability testing failed.
    CONCLUSION: Profiling cftDNA from peritoneal fluid is feasible, providing a significant amount of tumor DNA. This fast and reliable approach enables HRD testing, including BRCA1/2 mutations and genomic instability assessment. HRD testing on cfDNA from peritoneal fluid should be offered to all primary laparoscopy patients.
    Keywords:  Ascites; HRD; Ovarian cancer; ctDNA; shallowWGS
    DOI:  https://doi.org/10.1186/s12943-023-01864-1
  4. ESMO Open. 2023 Nov 01. pii: S2059-7029(23)01293-0. [Epub ahead of print]8(6): 102052
    Surgery and HIPEC in relapse for all patients with ovarian cancer?
    S P Hasson, I Ray-Coquard, C Marth, P Harter.
      
    DOI:  https://doi.org/10.1016/j.esmoop.2023.102052
  5. J Obstet Gynaecol Can. 2023 Nov 07. pii: S1701-2163(23)00641-2. [Epub ahead of print] 102278
    Opportunistic salpingectomy between 2017 and 2020: A descriptive analysis.
    Paramdeep Kaur, Khaye Rufin, Sarah J Finlayson, David G Huntsman, Janice S Kwon, Jessica N McAlpine, Dianne M Miller, Gillian E Hanley.
      OBJECTIVE: Opportunistic salpingectomy (OS) is the removal of fallopian tubes during another pelvic surgery for the purpose of ovarian cancer prevention. Herein, we describe the rates of OS at the time of hysterectomy and tubal sterilization between 2017 and 2020.METHODS: This study uses Canadian Institute of Health Information's Discharge Abstract Database and National Ambulatory Care Reporting System for all Canadian provinces and territories except for Quebec between the fiscal years 2017 and 2020. A descriptive analysis on all people aged 15 years and older who had hysterectomies or tubal sterilizations was conducted to determine the proportion of hysterectomies that included bilateral salpingectomy (OS) and the proportion of tubal sterilizations that were OS compared to tubal ligation.
    RESULTS: There were 174 006 people included in the study. The proportion of hysterectomies that included OS increased from 31.7% in 2017 to 39.9% by 2020. With respect to tubal sterilizations, rates of OS increased from 26.3% of all tubal sterilizations in 2017 to 42.5% in 2020. British Columbia remained the jurisdiction with the highest rates of OS, but rates increased significantly in many jurisdictions, particularly at the time of tubal sterilization.
    CONCLUSION: The rates of OS have continued to increase in all Canadian jurisdictions following the official Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendation to consider OS in 2015. Assuming that all tubal ligations could have been OS and 75% of hysterectomies with ovarian conservation could have included OS, our data indicate 76 932 missed opportunities for ovarian cancer prevention.
    Keywords:  Ovarian cancer; opportunistic salpingectomy; population-based administrative data; primary prevention
    DOI:  https://doi.org/10.1016/j.jogc.2023.102278
  6. Oncogene. 2023 Nov 09.
    Shallow whole genome re-sequencing to precisely predict benefit from PARP inhibitor.
    José L Sandoval, S Intidhar Labidi-Galy.
      
    DOI:  https://doi.org/10.1038/s41388-023-02871-8
  7. Lancet. 2023 Nov 03. pii: S0140-6736(23)01883-4. [Epub ahead of print]
    Pembrolizumab plus chemotherapy for pleural mesothelioma.
    Y C Gary Lee.
      
    DOI:  https://doi.org/10.1016/S0140-6736(23)01883-4
  8. Int J Gynecol Cancer. 2023 Nov 10. pii: ijgc-2023-004873. [Epub ahead of print]
    Circulating cell-free DNA as a diagnostic and prognostic marker for cervical cancer.
    Preetiparna Parida, Gayathri Baburaj, Mahadev Rao, Shirley Lewis, Rama Rao Damerla.
      Circulating cell-free DNA (cfDNA) is a promising tool for liquid biopsy-based tests. cfDNA has been reported to help in the diagnosis, quantification of minimal residual disease, prognosis, and identification of mutations conferring resistance in various types of cancers. Cervical cancer is the fourth most common cancer among women worldwide. High-risk human papillomavirus (hr-HPV) infections have been associated with almost all cervical cancers. Lack of HPV vaccines in national vaccination programs and irregular screening strategies in nations with low or moderate levels of human development index have led to cervical cancer becoming the second leading cause of cancer mortality in women. As HPV integration and overexpression of E6/E7 oncoprotein are crucial steps in the development of cancer, HPV cfDNA could potentially be used as a specific biomarker for the detection of cervical cancer. Many studies have used HPV cfDNA and other gene mutations or mRNA expression profiles for diagnosis and disease surveillance in patients with cervical cancer at various stages of disease progression. In this review we present an overview of different studies discussing the utility of cfDNA in cervical cancer and summarize the evidence supporting its potential use in diagnosis and treatment monitoring.
    Keywords:  Radiation Oncology; Uterine Cervical Neoplasms
    DOI:  https://doi.org/10.1136/ijgc-2023-004873
  9. Int J Gynecol Cancer. 2023 Nov 03. pii: ijgc-2023-004774. [Epub ahead of print]
    Low-grade serous ovarian carcinoma: a brief overview of the histopathologic features and differential diagnosis.
    Elizabeth C Kertowidjojo, Basile Tessier-Cloutier, Wendy P Veronica, Herman Chui.
      
    Keywords:  Carcinoma, Ovarian Epithelial; Pathology
    DOI:  https://doi.org/10.1136/ijgc-2023-004774
  10. Front Oncol. 2023 ;13 1305140
    Editorial: Translational research for better diagnosis and treatment of endometrial cancer.
    Andrea Romano, Andrzej Semczuk, Janina Tokarz, Tea Lanišnik Rižner.
      
    Keywords:  biomarkers; endometrial cancer; gynaecology; metabolomics; omics; proteomics
    DOI:  https://doi.org/10.3389/fonc.2023.1305140
  11. Nat Genet. 2023 Nov 09.
    Most large structural variants in cancer genomes can be detected without long reads.
    Zi-Ning Choo, Julie M Behr, Aditya Deshpande, Kevin Hadi, Xiaotong Yao, Huasong Tian, Kaori Takai, George Zakusilo, Joel Rosiene, Arnaud Da Cruz Paula, Britta Weigelt, Jeremy Setton, Nadeem Riaz, Simon N Powell, Klaus Busam, Alexander N Shoushtari, Charlotte Ariyan, Jorge Reis-Filho, Titia de Lange, Marcin Imieliński.
      Short-read sequencing is the workhorse of cancer genomics yet is thought to miss many structural variants (SVs), particularly large chromosomal alterations. To characterize missing SVs in short-read whole genomes, we analyzed 'loose ends'-local violations of mass balance between adjacent DNA segments. In the landscape of loose ends across 1,330 high-purity cancer whole genomes, most large (>10-kb) clonal SVs were fully resolved by short reads in the 87% of the human genome where copy number could be reliably measured. Some loose ends represent neotelomeres, which we propose as a hallmark of the alternative lengthening of telomeres phenotype. These pan-cancer findings were confirmed by long-molecule profiles of 38 breast cancer and melanoma cases. Our results indicate that aberrant homologous recombination is unlikely to drive the majority of large cancer SVs. Furthermore, analysis of mass balance in short-read whole genome data provides a surprisingly complete picture of cancer chromosomal structure.
    DOI:  https://doi.org/10.1038/s41588-023-01540-6
  12. Cancer Lett. 2023 Nov 01. pii: S0304-3835(23)00420-2. [Epub ahead of print] 216469
    Metronomic chemotherapy in ovarian cancer.
    Vikas Garg, Lalit Kumar.
      Translational research and the development of targeted therapies have transformed the therapeutic landscape in epithelial ovarian cancer (EOC) over the last decade. However, recurrent ovarian cancer continues to pose formidable challenges to therapeutic interventions, necessitating innovative strategies to optimize treatment outcomes. Current research focuses on the development of pharmaceuticals that target potential resistance pathways to DNA repair pathways. However, the cost and toxicity of some of these therapies are prohibitive and majority of patients lack access to clinical trials. Metronomic chemotherapy, characterized by the continuous administration of low doses of chemotherapeutic agents without long treatment breaks, has emerged as a promising approach with potential implications beyond recurrent setting. It acts primarily by inhibition of angiogenesis and activation of host immune system. We here review the mechanism of action of metronomic chemotherapy, as well as its current role, limitations, and avenues for further research in the management of epithelial ovarian cancer.
    Keywords:  Angiogenesis; Clinical trials; Drug repositioning; Drug repurposing; Immune system; Metronomic chemotherapy
    DOI:  https://doi.org/10.1016/j.canlet.2023.216469
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